Abstract
OBJECTIVE: Poly (ADP-ribose) polymerase (PARP) inhibitors, based on synthetic lethality, have demonstrated significant efficacy in tumors with homologous recombination repair (HRR) deficiencies but are limited by severe hematological toxicities. TSL-1502 is a glucuronide prodrug of a novel oral small-molecule PARP inhibitor that releases its active metabolite, TSL-1502M, specifically in tumor tissues. This phase I study aimed to evaluate the impact of food on the pharmacokinetics and safety of TSL-1502, guiding its clinical use. METHODS: Twenty healthy Chinese subjects were randomized into two groups (A and B, n = 10 each). In a two-period crossover design, participants received a single 200 mg oral dose of TSL-1502 under fasting or fed conditions. Plasma concentrations of TSL-1502 and TSL-1502M were measured using liquid chromatography-tandem mass spectrometry, and safety was assessed throughout. RESULTS: Food delayed the absorption of TSL-1502 but did not significantly affect its elimination half-life. The least-squares geometric mean ratios (fed/fasted) for AUC(0-t) and AUC0-∞ of TSL-1502 were 86.53% (71.23%-105.11%) and 88.36% (73.41%-106.35%), respectively. For TSL-1502M, the ratios were 90.03% (72.88%-111.22%) and 105.51% (93.51%-119.06%). Postprandial administration reduced TSL-1502 AUC(0-t) by 13.47%, AUC0-∞ by 11.64%, and Cmax by 56.58%. For TSL-1502M, AUC(0-t) decreased by 9.97%, AUC0-∞ increased by 5.51%, and Cmax decreased by 47.77%. All adverse events were grade I or II. CONCLUSION: Food delayed the absorption of TSL-1502 and substantially reduced its peak plasma concentration (Cmax), while AUC was moderately affected. TSL-1502 was well tolerated, and food did not affect its safety profile. These results suggest that TSL-1502 can be administered with or without food.